CH624128A5 - Process for the preparation of D-homosteroids - Google Patents

Abstract

D-Homosteroids with hormonal activity and the formula <IMAGE> in which the dotted lines in the A ring indicate optional C-C bonds; R<1> is hydrogen or methyl, R<3> is oxo or, if ring A is unsaturated, is oxo, ( alpha -H, beta -OH) or ( alpha -H, beta -O-acyl); and R<17a alpha > is lower alkyl, ethynyl, vinyl or propadienyl, are prepared in a manner known per se starting from the corresponding 17a-keto-D-homosteroids. The 17a beta -hydroxy- or 3,17a beta -dihydroxy-D-homosteroids of the formula I can be acylated, the D-homosteroids of the formula I can be etherified to give 17a beta -(C1-10-alkyl, benzyl, cyclohexylmethyl, cycloalkenyl or tetrahydropyranyl) ethers, a D-homosteroid of the formula I which is saturated or singly unsaturated in the A ring can be dehydrogenated to give a D-homosteroid of the formula I which is singly or doubly unsaturated in the A ring, a 3-acyloxy group present in a D-homosteroid of the formula I can be hydrolysed, and a 17a alpha -ethynyl group contained in a D-homosteroid of the formula I can be reduced to a vinyl group.

Description

The invention relates to a process for the preparation of new D-homosteroids of the formula

9V ™ 50

where the dotted lines in the A ring denote optional C-C bonds; R1 is hydrogen or methyl, R3 oxo or, if ring A is unsaturated, oxo, (a-H, ß-OH) or (a-H, / j-O-acyl); mean lower alkyl, ethynyl, vinyl or propadienyl.

The term “acyl” is intended in particular to denote organic acid residues, for example residues of alkane carboxylic acids containing up to 11 carbon atoms, in particular residues of lower alkane carboxylic acid (containing up to 7 carbon atoms), such as acetic acid, propionic acid, caproic acid, valeric acid , Oenanthic acid, undecylic acid; or oxalic acid, succinic acid, citric acid; or residues of aromatic carboxylic acids such as benzoic acid, phenylacetic acid, or phenoxyacetic acid; or heterocyclic carboxylic acids such as nicotinic acid; or cycloaliphatic carboxylic acids, such as cyclopentylpropionic acid.

Lower alkyl radicals can contain up to 7 carbon atoms and can be straight-chain or branched. Examples include methyl, ethyl, propyl, isopropyl, butyl and isomers thereof. Preferred lower alkyl radicals are methyl and ethyl. An alkyl radical R17ass can contain up to 10 carbon atoms. Examples of such radicals are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and decyl.

Cycloalkenyl radicals preferably contain 5-8 carbon atoms. Examples include cyclopenten-l-yl and cyclohexen-l-yl.

45

50

55

60

65

R3

Ii r 35

40

in which R1, R3 and the dotted lines in the A ring have the meaning given, with intermediate protection of a 3-keto group, with an organometallic compound which gives off a radical R17M.

One can mono- or diacylate a 3- or 17a / j-hydroxy- or 3,17a /? - dihydroxy-D-homosteroid of the formula I obtained by this process, and a 17a / j-hydroxy-D-homosteroid of the formula I etherify a 17a /> - (Cx _ 10-alkyl, benzyl, cyclohexymethyl, cycloalkenyl or tetrahydropyranyl) ether, a D-homosteroid of formula I saturated or monounsaturated in the A ring to form a single or double ring in the A ring Dehydrate unsaturated D-homosteroid of formula I, saponify a 3-acyloxy group present in a D-homosteroid of formula I and reduce a 17aa-ethynyl group contained in a D-homosteroid of formula I to the vinyl group.

The reaction of the 17a-keto group of a compound of formula II with an organometallic compound according to the above method can be carried out in a manner known per se. The organometallic compound can be a Grignard compound (e.g., ethylmagnesium bromide, methylmagnesium bromide, vinylmagnesium bromide) or an alkali metal organic compound such as sodium, potassium or lithium acetylide, or vinyl lithium. A 3-keto group which is present at the same time can be intermediate, e.g. B. as ketal, enol ether, enamine or semicarbazone.

The acylation of a 3- or 17a ^ free hydroxy group in a D-homosteroid of formula I can be achieved by treatment with a reactive acid derivative, e.g. B. an acid halide or acid anhydride, in the presence of a base such as pyridine or collidine.

1,2-dehydrogenation can be carried out in a manner known per se

624128

4th

with dehydrating agents such as selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, thallium triacetate or lead tetraacetate. The 1,2-dehydrogenation can also be microbiological, for example by means of Schizomycetes, in particular those of the Genera Arthrobacter, e.g. B. A. simplex ATCC 6946; Bacillus, e.g. B. B. lentus ATCC 13805 and B.sphaericus ATCC 7055; Pseudomonas, e.g. B. P. aeruginosa IFO 3505, Flavobacterium, e.g. B. flavenscens IFO 3058; Lactobacillus, e.g. B. L. brevis IFO 3345 and Nocardia, e.g. B. N. opaca ATCC 4276.

Double bonds in the 1,2 and 4,5 positions can be introduced simultaneously by bromination to give 2,4-dibromo-3-ketone and de-hydrobromination of the latter using lithium carbonate and lithium bromide in dimethylformamide.

A 4,5-double bond can also be introduced by brominating a 3-ketone steroid saturated in the A ring in glacial acetic acid to give the 2a, 4a-dibromo derivative and reducing this with chromium-II-chloride to the 4a-bromo compound. The latter compound can then be dehydro-brominated via the semicarbazone by treatment with succinic acid to give the A4-3 ketone.

The etherification of a 17a / 3-hydroxy group can e.g. B. by treatment with dihydropyran (for the preparation of the tetrahydropyranyl ether) or by treatment with a cycloalkanone ketal in the presence of a catalytic amount of acid, such as p-toluene sulfonic acid (for the preparation of a cycloalkenyl ether). A 3-oxo group is expediently protected in order to prepare a 17a-C1-j0-alkyl, benzyl or cyclohexylmethyl ether. Protection of the 3-oxo group is preferably accomplished by ketalization, e.g. B. with ethylene glycol in the presence of a catalytic amount of acid such as p-toluenesulfonic acid. The etherification of the 17a /? - hydroxy grappe can be converted into an alkali metal salt, e.g. B. the sodium salt, with a strong base, e.g. As sodium hydride, and reaction with a C1_10 alkyl, benzyl or cyclohexylmethyl halide, such as pentyl iodide, benzyl chloride or cyclohexyl methyl iodide, in a solvent such as dimethyl sulfoxide or benzene.

The saponification of 3-acyloxy groups can be carried out in a manner known per se. Acyloxy groups can e.g. B. with aqueous alcoholic bases, such as aqueous methanolic potassium carbonate. The hydrogenation of the 17aa ethynyl group can be accomplished in the presence of noble metal catalysts such as Pd / CaCOa and, expediently, a deactivator such as pyridine.

The starting materials for the preparation of the compounds of the formula I according to the invention can, if they are not known or their preparation is described here, be prepared by methods known per se or in analogy to the methods described below.

The compounds of formula I are hormonally active. Compounds of the formula I in which R17aa is lower alkyl are particularly androgenically / anabolically active. Compounds of the formula I in which R17aa is ethynyl, vinyl or propadienyl are particularly gestagenic and have an ovulation-inhibiting action.

The process products can be used as a remedy for. B. find in the form of pharmaceutical preparations use, which they in admixture with a suitable for enteral, percutaneous or parenteral application pharmaceutical, organic or inorganic inert carrier material, such as. B. water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils polyalkylene glycols, petroleum jelly, etc. contain. The pharmaceutical

Preparations can be in solid form, e.g. B. as tablets, dragées, suppositories, capsules, or in liquid form, for. B. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.

example 1

1. Production of the starting material:

3 /? - Acetoxy-D-homo-androst-5-en-17a-one was converted to 3/5-acetoxy-D-homo-5a-androstan-17a-one in ethanol with Pd / C as a catalyst, mp. 113 —115 °, reduced. This was brominated with copper bromide in methanol and converted into 3β-hydroxy-D-homo-androst-16-en-17a-one, mp. 177-179 ° by treatment with calcium carbonate in dimethylacetamide. Jones oxidation of this substance gave D-Ho-mo-5a-androst-16-en-3,17a-dione with a melting point of 200-202 ° (s22s = 8700).

2. The procedure

Reaction of the D-homo-5a-androst-16-en-3,17a-dione with methanol and catalytic amounts of p-toluenesulfonic acid at the reflux temperature gave 3,3-dimethoxy-D-homo-5a-an-drost-16-en- 17a-on, m.p. 125-127 °. A solution of 3.0 g of 3,3-dimethoxy-D-homo-5a-androst-16-en-17a-one was added to 70 ml of a 2-molar solution of methyl lithium in ether with stirring within 30 minutes 20 ml tetrahydrofuran and 20 ml ether. The solution was stirred at room temperature overnight and then worked up. 3.2 g of crude product were obtained, which was dissolved in 50 ml of acetone and then treated with a solution of 1.0 g of p-toluenesulfonic acid in 5 ml of water. The mixture was kept at room temperature for 2 hours, water was added and the mixture was extracted with methylene chloride. After chromatography on silica gel, the residue gave pure 17a /? -Hydroxy-17a-methyl-D-homo-5a-an-drost-16-enn-3-one, mp 211-214 °, [a] D25 = -52 ° (c = 0.1 in dioxane).

Example 2

In a manner analogous to Example 1

17a /? - hydroxy-17a-methyl-iD-homo-androsta-l, 4,16-trien-3-one, mp. 148-150 °,

17a /? -Hydroxy-17a-methyl-D-homo-androsta-4,16-dien-3-one, mp. 152-154 ° (acetone-hexane),

3ß, 17a /? - Dihydroxy-17a-methyl-D-homo-androsta-4,16-diene, mp. 137-141 ° and

17aa-ethynyl-17a /} - hydroxy-D-homo-androsta-4,16-dien-3-one, mp. 247-250 °.

Example 3

649 mg of 17aa-ethynyl-17a /} - hydroxy-D-homo-androsta-4,16-dien-3-one were dissolved in 40 ml of ethyl acetate and 5 ml of pyridine and, after addition of 300 mg of Pd / CaCOs, hydrogenated at normal pressure until 1.1 equivalent of hydrogen were absorbed. The catalyst was filtered off and the solvent evaporated in vacuo. The residue was recrystallized from acetone-hexane. Pure 17a / J-hydroxy-17aa-vinyl-D-homo-androsta-4,16-dien-3-one with a melting point of 120-122 ° was obtained. UV: £ 240 = 16500, [a] D250 = -69 ° (c = 0.1 in dioxane).

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Claims (9)

624128 2nd PATENT CLAIMS 1. Process for the production of D-homosteroids from formula 17act in which the dotted lines in the A ring denote optional C-C bonds; R1 is hydrogen or methyl, R3 oxo or, if ring A is unsaturated, oxo, (a-H, ß-OH) or (a-H, / J-O-acyl); and R17affl mean lower alkyl, ethynyl, vinyl or propadienyl, characterized in that a D-homosteroid of the formula R3 Ii in which R1, R3 and the dotted lines in the A ring have the meaning given, with intermediate protection of a 3-keto group with an organometallic compound which gives off a radical R 17 ° .beta. 2. The method according to claim 1, characterized in that starting from a D-homosteroid of the formula II obtained in the A-ring saturated or monounsaturated D-homosteroid of the formula I to a mono- or doubly unsaturated D-homosteroid in the A-ring of formula I dehydrated. 3. The method according to claim 1, characterized in that a 3-acyloxy group is saponified in a D-homosteroid of the formula I obtained from a D-homosteroid of the formula II. 4. The method according to claim 1, characterized in that one of a D-homosteroid of the formula II obtained D-homosteroid of formula I reduced the 17aa-ethynyl group to the viiiyl group. 5. The method according to claim 1, characterized in that compounds of formula I are prepared in which R1 represents hydrogen and R3 oxo and the ring A is a double bond; contains. 6. The method according to claim 1, characterized in that compounds of formula I are prepared in which Ri ™ is methyl or ethyl. 7. Process for the preparation of D-homosteroids of the formula 40 45 10th K M 17aa I ' 15 20th wherein the dotted lines in the A-ring denote optional C-C bonds: R1 is hydrogen or methyl, R3 'oxo or, if the ring A is unsaturated, oxo or (a-H, β-O-acyl); RmG mean acyl and R17aa lower alkyl, etinyl, vinyl or propadienyl, characterized in that a D-homosteroid of the formula 25th 30th 35 R: R 17aa wherein the dotted lines in the A-ring and R1, R3 and Ri7oa have the meanings given in claim 1, according to the method before. Claim 1 produces and then acylated the 17a-hydroxy group and an existing 3-hydroxy group. 8. The method according to claim 7, characterized in that compounds of the formula I 'are prepared in which R17ass is lower alkanoyl. 9. Process for the preparation of D-homosteroids of the formula 50 55 60 DÌ7aa in which the dotted lines in the A ring denote optional C-C bonds; R1 is hydrogen or methyl, R3 oxo 65 or, if ring A is unsaturated, oxo, (a-H, ß-OH) or (a-H, / J-O-acyl); R17i "ßC1_10-'alkyl, benzyl, cyclohexyl-methyl, cycloalkenyl or tetrahydropyranyl and R17a" lower alkyl, ethynyl, vinyl or propadienyl mean that 3rd 624128 characterized by being a D-homosteroid of the formula Rl7aa 110 15 wherein the dotted lines in the A-ring and R1, R3 and Riwo have the above meanings, produces by the method of claim 1 and then etherifies the 17a /? - hydroxy group accordingly. A preferred connecting group within the formula I are the compounds in which R1 represents hydrogen and R3 oxo and ring A contains a double bond. Furthermore, those compounds of the formula I are preferred in which R17 ° a is methyl or ethyl. Examples of compounds of formula I are la, 17aa-dimethyl-D-homo-androsta-4,16-dien-3-one, 3 /?, 17a /? -Dihydroxy-17a-methyl-D-homo-5a-androsta -1.16-dien, 17a /? -Hydroxy-17a-methyl-D-homo-5 «-androsta-l, 16-dien-3-one, 17a / J-hydroxy-la, 17a-methyl-D-homo-5a-androst-16-en-3-one, 17a /? - Hydroxy-17a-ethyl-D-homo-5a-androst-16-en-3-one, 17a «-ethyl-17a-hydroxy-la-methyl-D-homo-5a-androst-16-ene -3-one. According to the invention, the D-homosteroids of the formula I can be obtained by using a D-homo-steroid of the formula 20th 25th